Trisubstituted naphthylalkylamides for disorders of the melatoninergic system

ABSTRACT

The invention relates to a compound selected from those of formula (I):    &lt;IMAGE&gt;  (I)  in which R, R1, R2 and R3 are as defined herein for use in the treatment of a disorder of the melatoninergic system.

The present invention relates to novel derivatives of naphthalenestructure, the process for their preparation and the pharmaceuticalcompositions which contain them.

Patent EP 447,285 describes naphthalene derivatives which aremonosubstituted on the ring bearing the alkylamide chain. PatentApplication EP 530,087 describes naphthylalkylurea andnaphthylalkylthiourea derivatives which are also monosubstituted on thering bearing the alkylurea chain. These compounds possess manyadvantageous pharmacological activities as a result of their affinityfor melatonin receptors. Patent Application EP 562,956 describesnaphthalene derivatives, monosubstituted on the ring bearing thealkylamide chain, which exhibit an antagonist nature toward melatonin.Document DE 3,828,566 describes1-acetyl-4-(2-acetylaminoethyl)naphthalene, but exclusively as asynthesis intermediate.

Besides their beneficial action on circadian rhythm disorders (J.Neurosurg. (63), Sept. 1985, page 333) and on sleeping disorders(Psychopharmacology, 1990, 100, page 222), compounds acting on themelatoninergic system possess advantageous pharmacological properties onthe central nervous system, in particular anxiolytic properties(Neuropharmacology of Pineal Secretions, vol. 8, No.3-4, 1990, page272), antipsychotic properties (Neuropharmacology of Pineal Secretions,vol. 8, No.3-4, 1990, page 267), analgesic properties(Pharmacopsychiat., 20, 1987, page 222), for the treatment ofParkinson's disease (J. Neurosurg. (63), Sept. 1985, page 331) and forAlzheimer's disease (Brain Research, 528, 1990, page 173). Likewise,these compounds have shown an activity on some cancers (Melatonin -Clinical Perspectives, 1988, page 164-165), on ovulation (Science, vol.227, page 719-720), on immunomodulation (Adv. Pineal Research, vol. 5,1991) and on diabetes (Clinical endocrinology, 24, 1986, page 363).

The Applicant has discovered novel naphthalene derivatives,disubstituted on the ring bearing the alkylamide chain, which arepowerful ligands for the melatonin receptors.

More particularly, the invention relates to the compounds of formula(I): ##STR2## in which: R represents a hydrogen or a radical chosen fromalkyl, substituted alkyl and --O--R'; with R' representing a hydrogen oran alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, substituted cycloalkylalkyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, diphenylalkyl orsubstituted diphenylalkyl radical;

R₁ represents a hydrogen or an alkyl;

R₂ means a) ##STR3## in which X¹ represents a sulfur or oxygen atom andR₄₀ represents a hydrogen or a radical chosen from alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substitutedcycloalkylalkyl, alkenyl, substituted alkenyl, alkynyl and substitutedalkynyl; or b) ##STR4## in which X² represents a sulfur or an oxygen andR₄₁ represents a hydrogen or a radical chosen from alkyl, cycloalkyl andcycloalkylalkyl;

R₃ represents a radical chosen from:

(C₂ -C₆) alkyl,

substituted (C₂ -C₆) alkyl,

cycloalkylalkyl,

substituted cycloalkylalkyl,

alkenyl,

substituted alkenyl,

alkynyl,

substituted alkynyl,

hydroxyl in 3-position,

R₅ -alkyl-, with R₅ being substituted or unsubstituted and representinga radical chosen from pyridyl, phenyl, naphthyl, thienyl, furyl,pyrimidyl, indolyl, benzofuryl, benzothienyl, quinolyl and isoquinolyl;

R₆ --CO--O--,

and R₆ --CO--,

with R₆ representing a radical chosen from (C₁ -C₅)alkyl, substituted(C₁ -C₅)alkyl, cycloalkyl, substituted cycloalkyl, cycloalkyl(C₁-C₅)alkyl, substituted cycloalkyl(C₁ -C₅)alkyle, R₅ - and R₅ -alkyl-where R₅, being unsubstituted or substituted, is as defined above,

it being understood that the compound of formula (I) cannot beN-{2-[(4-acetyl)naphth-1-yl]ethyl}acetamide,

the terms "alkyl" and "alkoxy" denoting, except where otherwisementioned, linear or branched groups of 1 to 6 carbon atoms,

the terms "alkenyl" and "alkynyl" denoting unsaturated, linear orbranched groups of 2 to 6 carbon atoms,

the term "cycloalkyl" denoting a cyclic group of 3 to 8 carbon atoms,

the term "substituted" applied to "alkyl", "alkoxy", "alkenyl","alkynyl", "cycloalkyl" or "cycloalkylalkyl" means that these groups aresubstituted with one or more radicals chosen from alkyl, alkoxy andhalogen;

the term "substituted" associated with R₅ and with "phenyl","phenylalkyl" or "diphenylalkyl" means that these groups are substitutedwith one or more radicals chosen from alkyl, alkoxy, halogen, hydroxyland trifluoromethyl;

their enantiomers and diastereoisomers,

and their addition salts with a pharmaceutically acceptable acid orbase.

The invention relates, for example, to the compounds of formula (I) inwhich:

R₃ is attached to position 3 of the naphthalene ring

R₃ is a hydroxyl,

R₃ is a (C₂ -C₆)alkyl,

R₃ is a cycloalkylalkyl,

R₃ is a group R₅ -alkyl-,

R₃ is a group R₅ -alkyl- in which R₅ is a phenyl,

R₃ is a group R₆ -CO--O--,

R₃ is a group R₆ -CO--,

R₆ is a (C₁ -C₅) alkyl,

R₆ is a cycloalkyl,

R₆ is a cycloalkylalkyl,

R₆ is a phenyl,

R is attached to position 7 of the naphthalene ring,

R is a hydrogen,

R is a hydroxyl,

R is an alkyl,

R is an alkoxy,

R₁ is a hydrogen,

R₂ is a group --CO--R₄₀

R₂ is a group --CS--R₄₀,

R₄₀ is an alkyl,

R₄₀ is a cycloalkyl,

R₄₀ is an alkenyl,

R₂ is a group --CX--NH--R₄₁,

X is an oxygen,

X is a sulfur,

R₄₁ is an alkyl,

or R₄₁ is a cycloalkyl.

The invention preferably relates to the following compounds:

N-[2-(7-methoxy-3-benzoylnaphth-1-yl)ethyl]-acetamide,

N-[2-(7-methoxy-3-cyclopropylcarbonylnaphth-1-yl)-ethyl]acetamide,

N-[2-(7-methoxy-3-propionylnaphth-1-yl)ethyl]-acetamide,

N-[2-(7-methoxy-3-acetylnaphth-1-yl)ethyl]acetamide,

N-[2-(7-methoxy-3-acetylnaphth-1-yl)ethyl]cyclopropylcarboxamide,

N-[2-(7-methoxy-3-hydroxynaphth-1-yl)ethyl]-acetamide,

N-[2-(3,7-dihydroxynaphth-1-yl)ethyl]carboxamide,

N-[2-(7-methoxy-3-benzylnaphth-1-yl)ethyl]acetamide,

N-[2-(7-methoxy-3-ethylnaphth-1-yl)ethyl]acetamide,

N-[2-(7-methoxy-3-cyclopropylmethylnaphth-1-yl)-ethyl]acetamide,

N-[2-(7-methoxy-3-propylnaphth-1-yl)ethyl]acetamide,

N-[2-(7-methoxy-3-ethylnaphth-1-yl)ethyl]cyclopropylcarboxamide.

Among the pharmaceutically acceptable acids which may be used to form anaddition salt with the compounds of the invention, there may bementioned by way of examples and with no limitation being implied,hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, malicacid, maleic acid, fumaric acid, oxalic acid, methanesulfonic acid,ethanesulfonic acid, camphoric acid and citric acid.

Similarly, among the pharmaceutically acceptable bases which may be usedto form an addition salt, there may be mentioned sodium hydroxide,potassium hydroxide, calcium hydroxide or aluminum hydroxide, alkalimetal carbonates or alkaline-earth metal carbonates, and organic basessuch as triethylamine, benzylamine, diethanolamine, tert-butylamine,dicyclohexylamine and arginine.

In particular, the alkyl radicals present in the formula (I) may bechosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl and hexyl.

The alkoxy radicals present in the formula (I) may be chosen frommethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,tert-butoxy, pentyloxy and hexyloxy.

The halogens present in the formula (I) may be chosen from chlorine,bromine, iodine or fluorin. The cycloalkyl radicals present in theformula (I) may be chosen from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

The invention also covers the process for the preparation of thecompounds of formula (I), in which a compound of formula (II): ##STR5##in which R, R₁ and R₂ are as defined in the formula (I), is reacted witha compound of formula (III):

    R.sub.6 --COCl                                             (III)

in which R₆ is as defined in the formula (I),

in order to obtain a corresponding compound of formula (Ia): ##STR6## inwhich R, R₁, R₂ and R₆ are as defined above, which may be, if sodesired,

either subjected to an oxidation by a Baeyer-Villiger reaction, in orderto obtain a corresponding compound of formula (Ib): ##STR7## in which R,R₁, R₂ and R₆ are as defined above, and then if the --O--CO--R₆substituent is in 3-position subjected to a saponification in thepresence of sodium hydroxide, in order to obtain a correspondingcompound of formula (Ic): ##STR8## in which R, R₁ and R₂ are as definedabove, or subjected to a reduction by mercury and zinc, in the presenceof toluene and hydrochloric acid, in order to obtain a correspondingcompound of formula (Id): ##STR9## in which R, R₁, R₂ and R₆ are asdefined above, the compounds of formula (Ia), (Ib), (Ic) and (Id)forming the set of compounds of formula (I),

which compounds of formula (I) may be,

purified according to one or more purification methods chosen fromcrystallization, chromatography on silica gel, extraction, filtration,and passage on charcoal or resin,

separated, where appropriate, in pure form or in the form of a mixture,into their possible enantiomers or diastereoisomers,

or salified by a pharmaceutically acceptable acid or base.

More particularly, the invention relates to the process for thepreparation of the compounds of formula (I'), a particular case of thecompounds of formula (I) in which R₃ is in the 3-position ofnaphthalene, in which a compound of formula (II): ##STR10## in which R,R₁ and R₂ are as defined in the formula (I), is reacted with a compoundof formula (III):

    R.sub.6 --COCl                                             (III)

in which R₆ is as defined in the formula (I),

in order to obtain a corresponding compound of formula (Ia'): ##STR11##in which R, R₁, R₂ and R₆ are defined as above, which may be, if sodesired,

either subjected to an oxidation by a Baeyer-Villiger reaction, in orderto obtain a corresponding compound of general formula (Ib'):

in which R, R₁, R₂ and R₆ are as defined above, and then optionally##STR12## subjected to a saponification in the presence of sodiumhydroxide, in order to obtain a corresponding compound of formula (Ic'):##STR13## in which R, R₁ and R₂ are as defined above, or subjected to areduction by mercury and zinc, in the presence of toluene andhydrochloric acid, in order to obtain a corresponding compound offormula (Id'): ##STR14## in which R, R₁, R₂ and R₆ are as defined above,the compounds of formula (Ia'), (Ib'), (Ic') and (Id') forming the setof compounds of formula (I'),

which compounds of formula (I') may be, if so desired,

purified according to one or more purification methods chosen fromcrystallization, chromatography on silica gel, extraction, filtration,and passage on charcoal or resin,

separated, where appropriate, in pure form or in the form of a mixture,into their possible enantiomers or diastereoisomers,

or salified by a pharmaceutically acceptable acid or base.

The compounds of formula (Ia), (Ib), (Ic) and (Id) may also, if Rrepresents --OCH₃, be subjected to a demethylation reaction by borontribromide. More particularly, the compounds of formula (Ia'), (Ib'),(Ic') and (Id') may, if R represents --OCH₃, be subjected to ademethylation reaction by boron tribromide. The correspondinghydroxylated compounds obtained also form part of the compounds offormula (I) according to the invention.

The starting materials used in the process described above are eithercommercially available or readily accessible to a person skilled in theart, according to processes which are well known in the literature.Reference will more particularly be made, for the compounds of generalformula (II), to the descriptions of Patent EP 447,285 and PatentApplication EP 530,087.

The thiocarboxamide compounds are readily obtained by a person skilledin the art, in particular by the use of Lawesson's reagent.

The compounds of formula (I) possess very advantageous pharmacologicalproperties and are useful for the treatment of melatoninergic disorders.

The pharmacological study of the derivatives of the invention has, infact, shown that they were not toxic and were endowed with a very highselective affinity for the melatonin receptors and with considerableactivity on the central nervous system, and beneficial properties werenoticed in particular toward sleeping disorders, anxiolytic,antipsychotic and analgesic properties as well as advantageousproperties on microcirculation which make it possible to establish thatthe products of the invention are useful in the treatment of stress,sleeping disorders, anxiety, seasonal depressions, insomnia andtiredness due to jet lag, schizophrenia, panic attacks, melancholia,appetite regulation, psychotic disorders, epilepsy, Parkinson's disease,senile dementia, various disorders associated with normal orpathological ageing, migraine, memory loss and Alzheimer's diseases, aswell as cerebral circulatory disorders. In another field of activity, itappears that the products of the invention possess properties asovulation inhibitors and immunomodulators, and that they are capable ofbeing used in the treatment of certain hormone-dependent cancers.

The compounds will preferably be used in the treatment of seasonaldepression, sleeping disorders, cardiovascular pathologies, insomnia andtiredness due to time zone changes, and in appetite disorders andobesity.

For example, the compounds will be used in the treatment of seasonaldepressions and sleeping disorders.

The compounds of the invention also possess a very advantageousmetabolic profile.

Another subject of the present invention is the pharmaceuticalcompositions containing a compound of formula (I) or, where appropriate,one of its addition salts with a pharmaceutically acceptable acid orbase in combination with one or more pharmaceutically acceptableexcipients.

Among the pharmaceutical compositions according to the invention,mention may more particularly be made of those which are suitable fororal, parenteral, nasal, percutaneous or transcutaneous, rectal,perlingual, ocular or respiratory administration and in particularsimple or sugar-coated tablets, sublingual tablets, sachets, packets,gelatin capsules, glossettes, pills, suppositories, creams, ointments,dermal gels, and drinkable or injectable ampules.

The dosage varies depending on the age and weight of the patient, theroute of administration, the nature of the therapeutic indication, orpossible treatments which may be associated, and increases in graduateddoses between 0.1 mg and 1 g taken once or twice per 24 hours, moreparticularly 1 to 100 mg, for example 1 to 10 mg.

The examples which follow illustrate the invention but in no way implyany limitation thereof.

EXAMPLE 1: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-ACETAMIDE##STR15##

To a solution of 11 g (45.2 mmol) ofN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide and 7.7 g (57.7 mmol) ofAlCl₃ in 60 cm³ of nitrobenzene, add dropwise 57.9 mmol of benzoylchloride, at 12° C. and under nitrogen. Allow to react for 2 hours at12° C. and pour the reaction mixture onto ice. Extract withdichloromethane, dry over magnesium sulfate, concentrate and thenchromatograph the crude material on silica (eluent CH₂ Cl₂ /CH₃ OH:99/1).

The compound of Example 1 is obtained:

Yield: 34% Melting point: 92°-95° C. Recrystallization solvent :Toluene/hexane Molecular weight: 365.411 for C₂₂ H₂₁ NO₃ ; 1H₂ O

    ______________________________________                                        Microanalysis:                                                                               C %  H %                                                       ______________________________________                                        Calculated       72.30  6.34                                                  Found            72.55  6.30                                                  ______________________________________                                    

Infra-red: νN--H (amide): 3340 cm⁻¹ νC═O (ketone): 1660 cm⁻¹ νC═O(amide): 1625 cm⁻¹

NMR (DMSO-d₆) 300 MHz 1.84 ppm (singlet, 3H, (Hc)) 3.23 ppm (triplet,2H, (Ha)) 3.37 ppm (quartet, 2H, (Hb)) 4.00 ppm (singlet, 3H, (Hd)) 7.28ppm (doublet, 1H, (H₆), J₆₋₅ =9 Hz) 7.57-7.81 ppm (unresolved complex,7H, [H₂, H₄, H(A)]) 8.00 ppm (doublet, 1H, (H5), J₅₋₆ =9 Hz) 8.14 ppm(multiplet, 2H, (H₈, NH))

EXAMPLES 2 TO 15

By working as in Example 1 but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted on the amide function, the compounds of the followingexamples are obtained:

EXAMPLE 2: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 3: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]BUTYRAMIDE EXAMPLE4: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]PENTANAMIDE EXAMPLE 5:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]HEXANAMIDE EXAMPLE 6:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 7:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDE EXAMPLE8: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]CYCLOPENTYLCARBOXAMIDEEXAMPLE 9:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]CYCLOHEXYLCARBOXAMIDE EXAMPLE10: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-N'-METHYLUREA EXAMPLE11: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-N'-ETHYLUREA EXAMPLE 12:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-N'-PROPYLUREA EXAMPLE 13:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-N'-HEXYLUREA EXAMPLE 14:N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-N'-CYCLOPROPYLUREA EXAMPLE15: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]-N'-CYCLOHEXYLUREAEXAMPLES 16 TO 26

By working as in Example 1, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted in the 7-position of naphthalene and also, whereappropriate, suitably substituted on the amide function, the compoundsof the following examples are obtained:

EXAMPLE 16: N-[2-(3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 16 bis:N-[2-(7-ETHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 17:N-[2-(7-PROPOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 18:N-[2-(7-PENTOXY-3-BENZOYLNAPHTH-1l-YL)ETHYL]ACETAMIDE EXAMPLE 19:N-[2-(7-ALLYLOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 20:N-[2-(7-PROPARGYLOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 21:N-[2-(7-CYCLOPROPYLMETHYLOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 22: N-[2-(7-CYCLOHEXYLOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 23:N-[2-(7-CYCLOHEXEN-2-YLOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE24: N-[2-(7-BENZYLOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 25:N-[2-(3-BENZOYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDE EXAMPLE 26:N-[2-(3-BENZOYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDE EXAMPLE 27:N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]ACETAMIDE##STR16##

By working in the same way as in Example 1, but usingcyclopropanecarboxylic acid chloride for the acylation reaction, thecompound of Example 27 is obtained:

Yield: 29% Recrystallization solvent: cyclohexane Melting point: 152° C.Molecular weight: 309.349 for C₁₉ H₁₉ NO₃

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  73.28        6.79   4.49                                          Found       73.00        6.83   4.38                                          ______________________________________                                    

Infra-red: νN--H (amide): 3340 cm⁻¹ νC═O (ketone): 1660 cm⁻¹ νC═O(amide): 1630 cm⁻¹

NMR (DMSO-d₆) 1.05 ppm (doublet, 4H, (H_(d))) 1.80 ppm (singlet, 3H,(H_(c))) 3.05 ppm (triplet, 1H, (H_(e))) 3.20 ppm (triplet, 2H, (H_(a)))3.35 ppm (multiplet, 2H, (H_(b))) 4.00 ppm (singlet, 3H, (H_(f))) 7.30ppm (doublet, 1H, (H₆) J₅₋₆ =8.80 Hz) 7.70 ppm (singlet, 1H, (H₈)) 7.85ppm (singlet, 1H, (H₂ or H₄)) 8.05 ppm (doublet, 1H, (H₅) J₅₋₆ =8.80 Hz)8.13 ppm (signal, 1H, NH) 8.65 ppm (singlet, 1H (H₄ or H₂))

EXAMPLES 28 TO 33

By working as in Example 27, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted on the amide function, the compounds of the followingexamples are obtained:

EXAMPLE 28: N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]PROPIONAMIDE EXAMPLE 29:N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYL NAPHTH-1-YL)ETHYL]BUTYRAMIDEEXAMPLE 30: N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDE EXAMPLE 31:N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDE EXAMPLE 32:N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYL NAPHTH-1-YL)ETHYL]-N'-METHYLUREAEXAMPLE 33: N-[2-(7-METHOXY-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]-N'-PROPYLUREA EXAMPLES 34 TO 37

By working as in Example 27, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide for the compound suitablysubstituted in the 7-position of naphthalene and, where appropriate,suitably substituted on the amide function, the compounds of thefollowing examples are obtained:

EXAMPLE 34: N-[2-(3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 35:N-[2-(7-CYCLOPROPYLMETHYLOXY-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 36:N-[2-3-CYCLOPROPYLCARBONYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 37:N-[2(3-CYCLOPROPYLCARBONYL-NAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 38: N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]ACETAMIDE##STR17##

By working in the same way as in Example 1, but using propionyl chloridefor the acylation reaction, the compound of Example 38 is obtained:

Yield: 47% Recrystallization solvent: toluene Melting point: 141°-143°C. Molecular weight: 299.255 for C₁₈ H₂₁ NO₃

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  72.21        7.07   4.68                                          Found       72.51        6.99   4.52                                          ______________________________________                                    

Infra-red: νN--H (amide): 3380 cm⁻¹ νC═O (ketone): 1665 cm⁻¹ νC═O(amide): 1610 cm⁻¹

NMR (DMSO-d₆) 1.13 ppm (triplet, 3H, (H_(e))) 1.83 ppm (singlet, 3H,(H_(C))) 3.15 ppm (multiplet, 4H, (H_(a), H_(d))) 3.32 ppm (multiplet,2H, (H_(b))) 4.00 ppm (singlet, 3H, (H)) 7.30 ppm (resolved doublet, 1H,(H₆) J₆₋₅ =9.00 Hz, J₆₋₈ =2.25 Hz) 7.70 ppm (doublet, 1H, (H₈) J₂₋₆=2.25 Hz) 7.80 ppm (singlet, 1H, (H₂ or H₄)) 8.00 ppm (doublet, 1H, (H₅)J₅₋₆ =9.00 Hz) 8.15 ppm (triplet, 1H, (NH)) 8.50 ppm (singlet, 1H, (H₄or H₂))

EXAMPLES 39 TO 44

By working as in Example 38, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted on the amide function, the compounds of the followingexamples are obtained:

EXAMPLE 39: N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 40: N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]BUTYRAMIDEEXAMPLE 41:N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 42:N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 43: N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]-N'-METHYLUREAEXAMPLE 44: N-[2-(7-METHOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]-N'-PROPYLUREAEXAMPLES 45 TO 48

By working as in Example 38, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted in the 7-position of naphthalene and, where appropriate,suitably substituted on the amide function, the compounds of thefollowing examples are obtained:

EXAMPLE 45: N-[2-(3-PROPIONYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 46:N-[2-(7-CYCLOPROPYLMETHYLOXY-3-PROPIONYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 47: N-[2-(3-PROPIONYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 48: N-[2-(3-PROPIONYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 49: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE##STR18##

By working as in Example 1, using acetyl chloride for the acylationreaction, the compound of Example 49 is obtained:

Molecular weight: 285.346 for C₁₇ H₁₉ NO₃ Melting point: 154.5° C.

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  71.56        6.71   4.91                                          Found       71.41        6.67   4.89                                          ______________________________________                                    

EXAMPLE 50:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDE##STR19##

By working as in Example 1, usingN-[2-(7-methoxynaphth-1-yl)ethyl]cyclopropylcarboxamide and acetylchloride as starting materials, the compound of Example 50 is obtained.

Yield: 31% Melting point: 140°-141° C. Recrystallization solvent:toluene Molecular weight: 311.365 for C₁₉ H₂₁ NO₃

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  73.28        6.79   4.49                                          Found       73.08        6.74   4.43                                          ______________________________________                                    

Infra-red: νN--H (amide): 3360 cm⁻¹ νC═O (ketone): 1680 cm⁻¹ νC═O(amide): 1600 cm⁻¹

NMR (DMSO=d₆) 0.65 ppm (multiplet, 4H, (H_(d))) 2.65 ppm (singlet, 3H,(H_(c))) 3.20 ppm (triplet, 2H, (H_(a))) 3.40 ppm (multiplet, 2H,(H_(b))) 4.00 ppm (singlet, 3H, (H_(f))) 7.30 ppm (resolved doublet, 1H,(H₆) J₆₋₅ =8.90 Hz, J₆₋₈ =2.00 Hz) 7.60 ppm (doublet, 1H, (H₈) J₈₋₆=2.00 Hz) 7.80 ppm (singlet, 1H, (H₂ or H₄)) 8.00 ppm (doublet, 1H, (H₅)J₅₋₆ =8.90 Hz) 8.30 ppm (triplet, 1H, (NH))

EXAMPLES 51 TO 63

Working as in Example 49, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted on the amide function, the compounds of the followingexamples are obtained:

EXAMPLE 51: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 52: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]BUTYRAMIDE EXAMPLE53: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]PENTANAMIDE EXAMPLE 54:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]HEXANAMIDE EXAMPLE 55:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDE EXAMPLE56: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOPENTYLCARBOXAMIDEEXAMPLE 57:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOHEXYLCARBOXAMIDE EXAMPLE58: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]-N'-METHYLUREA EXAMPLE 59:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]-N'-ETHYLUREA EXAMPLE 60:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]-N'-PROPYLUREA EXAMPLE 61:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]-N'-HEXYLUREA EXAMPLE 62:N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]-N'-CYCLOPROPYLUREA EXAMPLE63: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]-N'-CYCLOHEXYLUREAEXAMPLES 64 TO 75

By working as in Example 49, but replacingN-[2-(7-methoxynaphth-1-yl)ethyl]acetamide by the compound suitablysubstituted in the 7-position of naphthalene and also, whereappropriate, suitably substituted on the amide function, the compoundsof the following examples are obtained:

EXAMPLE 64: N-[2-(3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 65:N-[2-(7-ETHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 66:N-[2-(7-PROPOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 67:N-[2-(7-PENTOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 68:N-[2-(7-ALLYLOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 69:N-[2-(7-PROPARGYLOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 70:N-[2-(7-CYCLOPROPYLMETHYLOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE71: N-[2-(7-CYCLOHEXYLOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE72: N-[2-(7-CYCLOHEXEN-2-YLOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 73: N-[2-(7-BENZYLOXY-3-ACETYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 74: N-[2-(3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 75: N-[2-(3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 76: N-[2-(7-METHOXY-3-ACETOXYNAPHTH-1-YL)ETHYL]ACETAMIDE##STR20##

To a solution of 2.8 g (9.81 mmol) ofN-[2-(7-methoxy-3-acetylnaphth-1-yl)ethyl]acetamide, according toExample 49, in 125 cm³ of methanol is added a solution of 7.6 g (12.3mmol) of monoperoxyphthalic acid magnesium salt in 100 cm³ of wateradjusted to pH 5 with 1N NaOH. Stir at room temperature for 24 hours.Evaporate off the methanol, add 1N NaHCO₃, extract with CH₂ Cl₂, dryover MgSO₄, filter and concentrate. The compound of Example 76 isobtained.

EXAMPLE 77: N-[2-(7-METHOXY-3-HYDROXYNAPHTH-1-YL)ETHYL]ACETAMIDE##STR21## EXAMPLE 77

Dissolve the residue obtained in Example 76, that is to sayN-[2-(7-methoxy-3-acetoxynaphth-1-yl)ethyl]acetamide, in 200 cm³ ofmethanol and treat with 250 cm³ of 0.05N NaOH for 1 hour at roomtemperature. Evaporate off the MeOH, bring to pH 12 with 1N NaOH,extract with CH₂ Cl₂, dry over MgSO₄, filter and concentrate.Chromatograph on silica eluting with CH₂ Cl₂ /MeOH : 98/2. 2.3 g (35%)of the compound of Example 77 are obtained.

Molecular weight: 259.307 Melting point: 154.8° C. Recrystallizationsolvent: CH₂ Cl₂

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  69.48        6.61   5.40                                          Found       68.75        6.40   5.54                                          ______________________________________                                    

EXAMPLE 78: N-[2-(3,7-DIHYDROXYNAPHTH-1-YL)ETHYL]ACETAMIDE ##STR22##

Dissolve 0.2 g (0.771 mmol) ofN-[2-(7-methoxy-3-hydroxynaphth-1-yl)ethyl]acetamide, according toExample 77, in 5 cm³ of anhydrous dichloromethane. Cool in a bath of iceand salt. Add dropwise 0.8 cm³ of 1M boron tribromide. Stir in ice atroom temperature for 4 hours. Add a further 0.8 cm³ of 1M borontribromide in CH₂ CL₂. Allow to stir overnight at room temperature.Bring to pH 8 with 1N NaOH. Extract with CH₂ Cl₂. Dry with MgSO₄.Evaporate off the solvent. Recover the product. Extract with methylethyl ketone. Dry over MgSO₄. Evaporate off the solvent. Purify theproduct on 30 g of silica. Elute with CH₂ Cl₂ /MeOH: 95/5. The productof Example 78 is obtained.

Molecular weight: 245.28 Melting point: 171°-175° C. Recrystallizationsolvents: CH₃ CN, MeOH

EXAMPLES 79 TO 87

By working as in Examples 76 to 78, but using the suitably substitutednaphthylalkylamide compound, the compounds of the following examples areobtained:

EXAMPLE 79: N-[2-(7-METHOXY-3-ACETOXYNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 80: N-[2-(7-METHOXY-3-HYDROXYNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 81: N-[2-(3,7-DIHYDROXYNAPHTH-1-YL)ETHYL]PROPIONAMIDE EXAMPLE82: N-[2-(7-METHOXY-3-ACETOXYNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 83:N-[2-(7-METHOXY-3-HYDROXYNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 84: N-[2-(3,7-DIHYDROXYNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 85:N-[2-(7-METHOXY-3-ACETOXYNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDE EXAMPLE86: N-[2-(7-METHOXY-3-HYDROXYNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 87: N-[2-(3,7-DIHYDROXYNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 88: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE##STR23##

A solution of 72 mg of mercuric chloride in 5.5 cm³ of water is added to3.6 g of zinc powder. Stir for 30 minutes. Allow to decant and removethe water.

Next, add 3.6 cm³ of water to this amalgam, then 3.6 cm³ of concentratedhydrochloric acid and then 5.26 mmol ofN-[2-(7-methoxy-3-benzoylnaphth-1-yl)ethyl]acetamide, prepared accordingto Example 1, and 25 cm³ of toluene.

Bring to reflux for 2 hours, extract the organic phase, wash with water,dry over magnesium sulfate, filter and evaporate to dryness.

The compound of Example 88 is obtained.

Yield: 35% Melting point: 85°-87° C. Recrystallization solvent: tolueneMolecular weight: 333.411 for C₂₂ H₂₃ NO₂

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  79.24        6.95   4.20                                          Found       78.93        6.94   4.22                                          ______________________________________                                    

Infra-red: νN--H (amide): 3220 cm⁻¹ νC═O (amide): 1610 cm⁻¹ νC═O(aromatic): 1590 cm⁻¹

NMR (DMSO-d₆) 1.80 ppm (singlet, 3H, (H_(c))) 3.00-3.45 ppm (unresolvedcomplex, 4H, (H_(a), H_(b))) 3.90 ppm (singlet, 3H, (O CH₃)) 4.00 ppm(singlet, 2H, (H_(d))) 7.00-7.80 ppm (unresolved complex, 10H, aromaticH) 8.00 ppm (signal, 1H, (NH))

EXAMPLES 89 TO 114

By working as in Example 88, but from the starting material of Examples2 to 26, the compounds of the following examples are obtained:

EXAMPLE 89: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 90: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]BUTYRAMIDE EXAMPLE91: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]PENTANAMIDE EXAMPLE 92:N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]HEXANAMIDE EXAMPLE 93:N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDE EXAMPLE94: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 95: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]CYCLOPENTYLCARBOXAMIDE EXAMPLE96: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]CYCLOHEXYLCARBOXAMIDEEXAMPLE 97: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]-N'-METHYLUREAEXAMPLE 98: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]-N'-ETHYLUREAEXAMPLE 99: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]-N'-PROPYLUREAEXAMPLE 100: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]-N'-HEXYLUREAEXAMPLE 101:N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]-N'-CYCLOPROPYLUREA EXAMPLE102: N-[2-(7-METHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]-N'-CYCLOHEXYLUREAEXAMPLE 103: N-[2-(3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 104:N-[2-(7-ETHOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 105:N-[2-(7-PROPOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 106:N-[2-(7-PENTOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 107:N-[2-(7-ALLYLOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 108:N-[2-(7-PROPARGYLOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 109:N-[2-(7-CYCLOPROPYLMETHYLOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE110: N-[2-(7-CYCLOHEXYLOXY-3l-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE111: N-[2-(7-CYCLOHEXEN-2-YLOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 112: N-[2-(7-BENZYLOXY-3-BENZYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 113: N-[2-(3-BENZYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 114: N-[2(3-BENZYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 115: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE##STR24##

Starting with N-[2-(7-methoxy-3-acetylnaphth-1-yl)ethyl]acetamide,prepared according to Example 49, and by working in the same way as inExample 88, the compound of Example 115 is obtained.

Molecular weight: 271.363 for C₁₇ H₂₁ NO₂ Melting point: 104°-105° C.

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  75.25        7.80   5.16                                          Found       74.99        8.12   5.08                                          ______________________________________                                    

EXAMPLES 116 TO 141

By working as in Example 115, but from the starting material of Examples50 to 75, the compounds of the following examples are obtained:

EXAMPLE 116: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]PROPIONAMIDEEXAMPLE 117: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]BUTYRAMIDE EXAMPLE118: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]PENTANAMIDE EXAMPLE 119:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]HEXANAMIDE EXAMPLE 120:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDE##STR25##

Yield: 38% Melting point: 116°-118° C. Recrystallization solvent:cyclohexane Molecular weight: 297.381 for C₁₉ H₂₃ NO₂

Infra-red: νN--H (amide): 3240 cm⁻¹ νC═O (amide): 1620 cm⁻¹

NMR (DMSO-d₆) 0.70 ppm (multiplet, 4H, (H_(d))) 1.25 ppm (triplet, 3H,(H_(f))) 1.60 ppm (multiplet, 1H, (H_(c))) 2.70 ppm (quartet, 2H,(H_(e))) 3.10 ppm (triplet, 2H, (H_(a))) 3.35 ppm (multiplet, 2H,(H_(b))) 3.90 ppm (singlet, 3H, (OCH₃)) 7.10 ppm (doublet, 1H, (H₆),J₆₋₅ =8.33 Hz) 7.15 ppm (singlet, 1H, (H₈)) 7.50 ppm (singlet, 2H, (H₂,H₄)) 7.70 ppm (doublet, 1H, (H₅), J₅₋₆ =8.33 Hz)) 8.20 ppm (triplet, 1H,(NH))

EXAMPLE 121:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDE EXAMPLE122: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOPENTYLCARBOXAMIDEEXAMPLE 123:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOHEXYLCARBOXAMIDE EXAMPLE124: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]-N'-METHYLUREA EXAMPLE125: N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]-N'-ETHYLUREA EXAMPLE 126:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]-N'-PROPYLUREA EXAMPLE 127:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]-N'-HEXYLUREA EXAMPLE 128:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]-N'-CYCLOPROPYLUREA EXAMPLE 129N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]-N'-CYCLOHEXYLUREA EXAMPLE 130:N-[2-(3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 131:N-[2-(7-ETHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 132:N-[2-(7-PROPOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 133:N-[2-(7-PENTOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 134:N-[2-(7-ALLYLOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 135:N-[2-(7-PROPARGYLOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE 136:N-[2-(7-CYCLOPROPYLMETHYLOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE137: N-[2-(7-CYCLOHEXYLOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE EXAMPLE138: N-[2-(7-CYCLOHEXEN-2-YLOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 139: N-[2-(7-BENZYLOXY-3-ETHYLNAPHTH-1-YL)ETHYL]ACETAMIDEEXAMPLE 140: N-[2-(3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLCARBOXAMIDEEXAMPLE 141: N-[2-(3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOBUTYLCARBOXAMIDEEXAMPLE 142:N-[2-(7-METHOXY-3-CYCLOPROPYLMETHYLNAPHTH-1-YL)ETHYL]ACETAMIDE ##STR26##

Starting withN-[2-(7-methoxy-3-cyclopropylcarbonylnaphth-1-yl)ethyl]acetamide,prepared according to Example 27, and by working in the same way as inExample 88, the compound of Example 142 is obtained.

Yield: 37.5% Melting point 89°-90° C. Recrystallization solvent:cyclohexane Molecular weight: 301.885 for C₁₉ H₂₃ NO₂ +1/4 H₂ O

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  75.58        7.84   4.63                                          Found       75.65        7.74   4.49                                          ______________________________________                                    

Infra-red: νN--H (amide): 3240 cm⁻¹ νC═O (amide): 1625 cm⁻¹

NMR (DMSO-d₆) 0.20 ppm (multiplet, 2H, (H_(g))) 0.50 ppm (multiplet, 2H,(H_(f))) 1.05 ppm (multiplet, 1H, (H_(e))) 1.85 ppm (singlet, 3H,(H_(c))) 2.60 ppm (doublet, 2H, (H_(d)), J=6.84 Hz) 3.10 ppm (triplet,2H, (H_(a))) 3.30 ppm (multiplet, 2H, (H_(b))) 3.90 ppm (singlet, 1H,(OCH₃)) 7.15 ppm (doubled doublet, 1H, (H₆), J₆₋₅ =8.90 Hz, J₆₋₈ =2.40Hz) 7.25 ppm (singlet, 1H, (H₈), J₈₋₆ =2.40 Hz) 7.55 ppm (multiplet, 2H,(H₂, H₄ Hz)) 7.80 ppm (doublet, 1H, (H₅), J₅₋₆ =8.90 Hz) 8.10 ppm(triplet, 1H, (NH))

EXAMPLE 143: N-[2-(7-METHOXY-3-PROPYLNAPHTH-1-YL)ETHYL]ACETAMIDE##STR27##

Starting with N-[2-(7-methoxy-3-propionylnaphth-1-yl)ethyl]acetamide,prepared according to Example 38, and by working in the same way as inExample 88, the compound of Example 143 is obtained.

Yield: 60% Melting point: 80°-82° C. Recrystallization solvent:petroleum ether Molecular weight: 285.371 for C₁₈ H₂₃ NO₂

    ______________________________________                                        Microanalysis:                                                                          C %        H %    N %                                               ______________________________________                                        Calculated  75.75        8.12   4.91                                          Found       75.46        7.95   4.90                                          ______________________________________                                    

Infra-red: νN--H (amide): 3230 cm⁻¹ νC═O (amide): 1620 cm⁻¹ νC═C(aromatic): 1600 cm⁻¹

NMR (DMSO-d₆) 0.90 ppm (triplet, 3H, (H_(f)), J=8.35 Hz) 1.65 ppm(multiplet, 2H, (H_(e))) 1.80 ppm (singlet, 3H, (H_(c))) 2.65 ppm(triplet, 2H, (H_(d)), J=7.49 Hz) 3.10 ppm (triplet, 2H, (H_(a))) 3.30ppm (multiplet, 2H, (H₂)) 3.90 ppm (singlet, 3H, (OCH₃)) 7.10 ppm(multiplet, 2H, (H₆, H₂)) 7.50 ppm (singlet, 1H, (H₄)) 7.55 ppm(doublet, 1H, (H₈), J₈₋₆ =1.95 Hz) 7.75 ppm (doublet, 1H, (H₅), J₅₋₆=8.39 Hz) 8.10 ppm (triplet, 1H, (NH))

EXAMPLES 144 TO 148

By working as in Examples 1, 49, 50, 115 and 120, but starting with thecorresponding thiocarboxamide compounds, the compounds of the followingexamples are obtained:

EXAMPLE 144: N-[2-(7-METHOXY-3-BENZOYLNAPHTH-1-YL)ETHYL]THIOACETAMIDEEXAMPLE 145: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]THIOACETAMIDEEXAMPLE 146: N-[2-(7-METHOXY-3-ACETYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLTHIOCARBOXAMIDE EXAMPLE 147:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]THIOACETAMIDE EXAMPLE 148:N-[2-(7-METHOXY-3-ETHYLNAPHTH-1-YL)ETHYL]CYCLOPROPYLTHIOCARBOXAMIDEPHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION

EXAMPLE A: STUDY OF THE ACUTE TOXICITY

The acute toxicity was assessed after oral administration to batches of8 mice (26 2 grams). The animals were observed at regular intervals inthe course of the first day and daily for the two weeks following thetreatment. The LD₅₀ causing the death of 50% of the animals wasevaluated. The LD₅₀ of the products tested is greater than 1000 mg.kg⁻¹for the compounds studied, which indicates the low toxicity of thecompounds of the invention.

EXAMPLE B: FOUR PLATE TEST

The products of the invention are administered via the esophagus tobatches of ten mice. One batch receives gum syrup. 30 minutes afteradministration of the products to be studied, the animals are placed inrooms the floor of which comprises four metal plates. Each time that theanimal passes from one plate to another, it receives a mild electricshock (0.35 mA). The number of passages is recorded over one minute.After administration, the compounds of the invention significantlyincrease the number of passages, which shows the anxiolytic activity ofthe derivatives of the invention.

EXAMPLE C: ACTIVITY OF THE PRODUCTS OF THE INVENTION ON ISCHEMICMICROCIRCULATION

The experimental study was performed on the cremaster muscles of malerats (Sprague-Dawley) after ligature of the common iliac artery.

The muscles were placed in a transparent chamber and infused with asolution of bicarbonate buffer equilibrated with a CO₂ /N₂ 5/95% gaseousmixture. The speed of the red corpuscles and the diameter of the firstor second order arterioles irrigating the cremaster were measured, andthe arterial-blood flow was calculated. Identical information wasobtained for four types of venule.

The same type of measurement was carried out simultaneously:

on the cremaster infused normally,

on the ligatured cremaster, that is to say the ischemic cremaster 2, 7,14 and 21 days after ligature.

Two groups of animals were studied:

a control group without treatment,

a group treated orally with a product of the invention, in an amount of0.1 mg.kg⁻¹ per day.

No difference was observed in the speed of the corpuscles nor in theblood vessel diameter in the cremaster muscles irrigated normally in thetreated animals with respect to the control animals.

On the contrary, the mean diameter of the arterioles in the ischemiccremaster muscle was enhanced in the treated animals with respect to thecontrol animals. The speed of the red corpuscles was standardized by atreatment for 21 days.

Indeed, in the treated animals, the speed of the red corpuscles and theblood flow measured 7 days after the ligature show no significantdifference with the values obtained in the non-ischemic cremaster. Theseresults are obtained without modification of the arterial pressure.

These results indicate that chronic treatment with a compound of theinvention improves the blood irrigation and microcirculation of theischemic regions.

EXAMPLE D: STIMULATION OF THE IMMUNE RESPONSES

Red corpuscles from sheep were administered to groups of six mice. Thesegroups of mice were subsequently treated subcutaneously with thecompounds of the invention for six days and a control group was treatedwith a placebo. The mice were subsequently left to rest for four weeksand then received a repeat injection of sheep red corpuscles withoutreceiving repeat administrations of product of the invention. The immuneresponse was evaluated 3 days after the repeat injection. It isstatistically higher in the group treated with the compounds of theinvention.

EXAMPLE E: EFFECTS OF THE COMPOUNDS OF THE INVENTION ON THE CIRCADIANSRHYTHMS OF LOCOMOTOR ACTIVITY

The involvment of melatonin in the entrainment, by light-dark cycle, ofmost of the physiological and biochemical circadian rhythms allowed toestablish a pharmacological model for the search of melatoninergicligands.

The effects of the compounds of the invention are tested on severalparameters and particularly on the circadian rhythms of locomotoractivity, which represent a reliable marker of the endogenous circadianclock activity.

PROTOCOL:

One-month old male Long Evans rats were subjected to a daily cycle of 12h light/12 h darkness (LD 12: 12) for 2-3 weeks, being maintained incages equipped with running wheels linked to a recording system in orderto detect and note locomotor activity phases as well as circadianrhythms.

They are then kept under constant darkness until a stable free-runningrhythm was established, and after this establishment, rats were thengiven daily an administration of the tested compound.

The reports are carried out with activity rhythm visualization:

activity rhythms entrainment under the daily cycle (LD 12: 12).

disparition of the rythm entrainment under constant darkness

entrainment by the daily administration of the tested compound;

RESULTS:

Taken together, the results evidence the therapeutic interest of thecompounds of the invention as chronobiotic for circadian rhythmdisorders.

EXAMPLE F: DEMONSTRATION OF THE ANALGESIC ACTIVITY

Research into the activity on pain was performed in mice (23-25 g)according to a procedure derived from the technique described bySIEGMUND (Siegmund E. A., R. A. Cadmus & Golu, J. Pharm. Exp. Ther. 119,1874, 1954). The mice, randomly distributed into batches of 12 animals,received the treatment orally (excipient for the controls) 1 hour beforeintraperitoneal injection of an aqueous-alcoholic 0.02% solution ofphenyl-p-benzoquinone (Sigma). The number of stretches is countedbetween the 5th and 10th minute after the injection.

It is apparent that the compounds of the invention possess an analgesicactivity.

EXAMPLE G: TEST OF BINDING TO THE MELATONIN RECEPTORS ON SHEEP TUBERALISPARS

The binding of the compounds of the invention to the melatonin receptorswas performed, according to the standard techniques, on sheep ParsTuberalis, as described in "Journal of Neuroendocrinology, vol. 1, No.1,1989".

It appears that the compounds of the invention bind very specifically tothe melatonin receptors, with an affinity which is superior to that ofmelatonin itself.

EXAMPLE H: TEST OF COMPETITION FOR THE MELATONIN RECEPTORS ON GALLUSDOMESTICUS CHICK BRAIN CELL MEMBRANES

The animals used are 12-day-old chicks (Gallus domesticus). They aresacrificed between 1 pm and 5 pm on the day of their arrival. The brainsare rapidly removed and frozen at -200° C. and then stored at -80° C.The membranes are prepared according to the method described by Yuan andPang (1991). The binding of melatonin to the membranes is performedaccording to a procedure established by Rivkees et al. (1989). Briefly,[¹²⁵ I]-melatonin is incubated in the presence of the membranes in asolution buffered at pH 7.4 for 60 min at 25° C. At the end of thisperiod, the membrane suspension is filtered (Whatman GF/C). Theradioactivity retained on the filter is determined using an LS 6000Beckman® liquid scintillation counter.

The products used are:

2 [¹²⁵ I]-melatonin

melatonin

usual materials

original molecules

In the primary screening, the molecules are tested at 2 concentrations(10⁻⁷ and 10⁻⁵ M). Each result is the average of n=3 independentmeasurements. The active molecules selected according to the results ofthe primary screening formed the subject of a quantitative determinationof their effectiveness (IC₅₀). They are used at 10 differentconcentrations.

Thus, the IC₅₀ values found for the preferred compounds of theinvention, which correspond to the values of the affinity, show that thebinding of the compounds tested to the melatoninergic receptors is,surprisingly, very powerful.

EXAMPLE I: PHARMACEUTICAL COMPOSITION: TABLETS

Tablets containing a 5 mg dose ofN-[2-(7-methoxy-3-ethylnaphth-1-yl)ethyl]acetamide. Formulation toprepare 1000 tablets.

N-[2-(7-methoxy-3-ethylnaphth-1-yl)ethyl]acetamide 5 g Wheat starch 15 gCorn starch 15 g Lactose 15 g Magnesium stearate 2 g Silica 1 gHydroxypropyl cellulose 2 g

We claim:
 1. A compound of formula (I): ##STR28## in which: R representshydrogen or a radical chosen from alkyl, substituted alkyl and --O--R';with R' representing hydrogen or a radical selected from alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl,substituted cycloalkylalkyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, diphenylalkyl and substituted diphenylalkyl;R₁represents hydrogen or alkyl; R₂ represents a) ##STR29## in which X¹represents sulfur or oxygen and R₄₀ represents hydrogen or a radicalchosen from alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl; or b) ##STR30## inwhich X² represents sulfur or oxygen and R₄₁ represents hydrogen or aradical chosen from alkyl, cycloalkyl and cycloalkylalkyl; R₃ representsa radical chosen from:(C₂ -C₆) alkyl, substituted (C₂ -C₆) alkyl,cycloalkylalkyl, substituted cycloalkylalkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, hydroxyl in 3-position, R₅-alkyl-, with R₅ being substituted or unsubstituted and representing aradical chosen from phenyl and naphthyl; R₆ --CO--O--, and R₆--CO--,with R₆ representing a radical chosen from (C₁ -C₅)alkyl,substituted (C₁ -C₅)alkyl, cycloalkyl, substituted cycloalkyl,cycloalkyl(C₁ -C₅)alkyl, substituted cycloalkyl(C₁ -C₅)alkyl, R₅ - andR₅ -alkyl- where R₅, being unsubstituted or substituted, is as definedabove, it being understood that the compound of formula (I) cannot beN-{2-[(4-acetyl)naphth-1-yl]ethyl}acetamide, wherein the terms "alkyl"and "alkoxy" denoting inclusively, except where otherwise mentioned,linear or branched groups of 1 to 6 carbon atoms, the terms "alkenyl"and "alkynyl" denoting inclusively unsaturated, linear or branchedgroups of 2 to 6 carbon atoms, the term "cycloalkyl" denotinginclusively a cyclic group of 3 to 8 carbon atoms, the term"substituted", applied to "alkyl", "alkoxy", "alkenyl", "alkynyl","cycloalkyl" or "cycloalkylalkyl", means that these groups aresubstituted with one or more radicals chosen from alkyl, alkoxy andhalogen; the term "substituted" associated with R₅ and with "phenyl","phenylalkyl" or "diphenylalkyl" means that these groups are substitutedwith one or more radicals chosen from alkyl, alkoxy, halogen, hydroxyland trifluoromethyl; their enantiomers and diastereoisomers, and theiraddition salts with a pharmaceutically acceptable acid or base.
 2. Acompound of claim 1, which isN-[2-(7-methoxy-3-benzoylnaphth-1-yl)ethyl]acetamide.
 3. A compound ofclaim 1, which is N-[2-(7-methoxy-3-acetylnaphth-1-yl)ethyl]acetamide.4. A compound of claim 1, which isN-[2(7-methoxy-3-acetylnaphth-1-yl)ethyl]cyclopropylcarboxamide.
 5. Acompound of claim 1, which isN-[2(7-methoxy-3-ethylnaphth-1-yl)ethyl]acetamide.
 6. A compound ofclaim 1, which is N-[2(7-methoxy-3-propylnaphth-1-yl)ethyl]acetamide. 7.A compound of claim 1 which isN-[2(7-methoxy-3-hydroxynaphth-1-yl)ethyl]acetamide.
 8. A compound ofclaim 1 which isN-[2-(7-methoxy-3-cyclopropylcarbonylnaphth-1-yl)ethyl]acetamide.
 9. Acompound of claim 1 which isN-[2-(7-methoxy-3-acetoxynaphth-1-yl)ethyl]acetamide.
 10. A compound ofclaim 1 which is N-[2-(7-methoxy-3-hydroxynaphth-1-yl)ethyl]acetamide.11. A compound of claim 1 which isN-[2-(3,7-dihydroxynaphth-1-yl)ethyl]acetamide.
 12. A compound of claim1 which N-[2-(7-methoxy-3-benzylnaphth-1-yl)ethyl]acetamide.
 13. Acompound of claim 1 which isN-[2-(7-methoxy-3-ethylnaphth-1-yl)ethyl]cyclopropylcarboxamide.
 14. Acompound of claim 1 which isN-[2-(7-methoxy-3-cyclopropylmethylnaphth-1-yl)ethyl]acetamide.
 15. Apharmaceutical composition useful in treating sleep disorders containinga compound of claim 1 in combination with one or morepharmaceutically-acceptable excipients.
 16. A method of treating amammal afflicted with a disorder of the melatoninergic system comprisingthe step of administrating to said mammal an effective amount of acompound according to claim 1 for alleviation of said disoder.
 17. Amethod of treating a mammal afflicted with a sleeping disordercomprising the step of administering to said mammal an effective amountof a compound according to claim 1 for alleviation of said disorder.